Process automation has become an essential element of all modern crystallography facilities. Robotic equipment allows crystals of biological macromolecules to be produced in greater numbers and rapidly mounted thus resulting in more efficient utilization of valuable X-ray resources. The need to maximize the productivity of these resources becomes more acute with the accelerating pace of research in the fields of rational drug discovery and structural genomics. Despite impressive technological progress, serious rate-limiting manual operations still persist in the crystallization sequence. These operations, commonly referred to as }bottlenecks}, have thus far resisted automation. The most serious of these bottlenecks are those tasks associated with crystal harvesting: the complex, ultra-precise motions required to retrieve a crystal from its incubation well exceed the capabilities of standard industrial robotics. The need to perform these manipulations on crystals submerged in mother liquors with a wide range of viscosities presents additional complications. A fully automated system capable of effectively addressing these challenges would provide researchers with a critical enabling technology. The Square One believes that recent advances in micromanipulation, machine vision and adaptive operator control now hold the promise for an integrated robotic system capable of consolidating all of the tasks associated with crystal harvesting. As envisioned, this Universal Micromanipulation Robot (UMR) will possess the resolution, accuracy and dexterity to effectively operate in the micron-scale realm of the smallest crystals. However, it will also have the range of motion and payload capacity needed to perform other essential process tasks. An end-effector exchange capability will allow the UMR to harvest crystals, apply cryobuffers and ligands, execute both micro- and macro-seeding operations and transfer samples to storage cassettes submerged in liquid nitrogen. Square One proposes an applied research program, conducted in cooperation with the University of Wyoming under the STTR program, which will demonstrate the functionality of a UMR work cell and establish its ability to operate without user intervention. Square One intends to build upon its Phase I success during the Phase II development effort. The goal is to produce a fully-realize autonomous version of the UMR that effectively addresses the needs of the crystallography user community and is ready for commercial production. PUBLIC HEALTH RELEVANCE: Structure guided drug discovery plays an increasingly important role in the development of therapeutic agents. High-throughput, autonomous robotic harvesting of fragile protein drug target crystal will address the last major bottleneck in the protein crystallography process. Overcoming this bottleneck will greatly streamline the characterization of target structures and contribute directly to the fight against major human diseases.